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(BQ) Part 2 book Fundamentals of renal pathology presentation of content: Vascular diseases, tubulointerstitial diseases, plasma cell dyscrasiasand associated renal diseases, renal transplant pathology.
Part V Vascular Diseases Nephrosclerosis and Hypertension 10 Arterionephrosclerosis Introduction/Clinical Setting Approximately 60 million people in the United States have hypertension Many are undiagnosed or untreated Different populations have different risks and different consequences of hypertension Increased hypertension is seen with aging, positive family history, African-American race, and exogenous factors such as smoking Although African-Americans make up only 12 % of the US population, they are fivefold overrepresented among patients with end-stage renal disease (ESRD) presumed due to hypertension [1, 2] Hypertension is associated with significant morbidity and mortality due both to cardiovascular and renal diseases [1–5] Essential hypertension is diagnosed when no cause is found Hypertension may also be secondary to various hormonal abnormalities, including excess aldosterone, norepinephrine, or epinephrine, or produced from adrenal cortical, medullary, or other tumors; renin-producing tumors; or hypercalcemia or hyperparathyroidism Other secondary causes include neurogenic, iatrogenic, and structural lesions (e.g., coarctation of the aorta) Renal hypertension refers to hypertension secondary to renal disease Chronic renal disease is the most common form of secondary hypertension (5–6 % of all hypertension) The kidneys modulate blood pressure in several ways: They modulate salt/water balance under the influence of aldosterone The kidney is also a major site of renin production, which allows generation of angiotensin II, an important vasoconstrictor and stimulus for aldosterone secretion In renovascular disease (i.e., stenosis of the renal artery), renal ischemia is thought to be the stimulus that increases renin-angiotensin system activity, thereby increasing systemic blood pressure In renal parenchymal disease, multiple factors contribute to increased blood pressure The decreased mass of functioning nephrons leads to a decrease in the glomerular filtration rate (GFR), leading to increased extracellular volume and increased angiotensin, aldosterone, and other vasoactive substances A.B Fogo et al., Fundamentals of Renal Pathology, DOI 10.1007/978-3-642-39080-7_10, © Springer-Verlag Berlin Heidelberg 2014 125 126 10 Nephrosclerosis and Hypertension The most common complications in untreated hypertension are cardiac, renal, and retinal disease Half of hypertensive patients die of cardiac disease, 10–15 % of cerebrovascular disease, and about 10 % of kidney failure Treatment to decrease blood pressure reduces mortality and especially reduces the incidence of cerebrovascular accidents Hypertension accelerates the decline in GFR characteristic of many chronic kidney diseases, whether the primary cause is hypertension associated or not Chronic kidney disease is common, affecting 195,000 Americans, with 45,000 new patients enrolled in end-stage treatment Medicare programs yearly It has been postulated that direct transmission of increased blood pressure to the glomerulus increases injury Other mechanisms may also play a role, however, since antihypertensive drugs have benefit even in nonhypertensive patients with chronic kidney disease (see below) Recent studies point to strong genetic factors linked to risk of hypertension-associated kidney injury, although mechanisms are not yet elucidated Pathologic Findings Gross Findings/Light Microscopy “Benign” nephrosclerosis results in small kidneys with finely granular surface and thinned cortex in late stages Malignant (accelerated) nephrosclerosis grossly shows petechial hemorrhage of the subcapsular surface, with mottling and occasional areas of infarct Microscopically, in “benign” arterionephrosclerosis there is vascular wall medial thickening with frequent afferent arteriolar hyaline deposits and varying degree of intimal fibrosis The hyalinization is due to endothelial injury and increased pressure, leading to an insudate of plasma macromolecules There are associated focal glomerular ischemic changes with variable thickening and wrinkling of the basement membrane and/or global sclerosis, tubular atrophy, and interstitial fibrosis (Fig 10.1) Global sclerosis more commonly is of the obsolescent type, with fibrous material obliterating Bowman’s space Solidified glomeruli, where the tuft is globally sclerosed without collagen in Bowman’s space, has been called “decompensated” arterionephrosclerosis Secondary focal segmental glomerulosclerosis (FSGS) may also occur, often with associated glomerular basement membrane (GBM) corrugation and filling of Bowman’s space with fibrous material [4–10] These morphologic features hint that the segmental sclerotic process is secondary to hypertension-associated injury, rather than idiopathic FSGS The lesions associated with accelerated hypertension consist of mucoid change of the arterioles, often with red blood cell (RBC) fragments within the wall In malignant hypertension, arterioles show fibrinoid necrosis, and interlobular arteries have a concentric onion-skin pattern of intimal proliferation and fibrosis, overlapping with the appearance of scleroderma and chronic thrombotic microangiopathy (Fig 10.2) (see below) There is proportional tubulointerstitial fibrosis in arterionephrosclerosis Arterionephrosclerosis 127 Fig 10.1 Arterial and arteriolar medial thickening, intimal and interstitial fibrosis, tubular atrophy, and global sclerosis in arterionephrosclerosis (PAS) Fig 10.2 Vascular fibrinoid necrosis and thrombosis in malignant hypertension (Jones silver stain) Immunofluorescence may show trapping of IgM and C3 in glomeruli, but there are no immune complex-type deposits In malignant hypertension, fibrin/fibrinogen staining may be present in necrosed arterioles/arteries and injured glomeruli 128 10 Nephrosclerosis and Hypertension Electron microscopy confirms the corrugated, wrinkled GBM and ischemic changes with increased lamina rara interna but without immune deposits Hyaline may be present in sclerosed segments Some foot process effacement of podocytes may also be present, but it is usually not extensive Although none of the above lesions are pathognomonic, the constellation of these changes in the absence of other lesions of primary glomerular disease is indicative of arterionephrosclerosis Etiology/Pathogenesis Hypertension has been presumed to cause end-organ damage in the kidney, and hypertension undoubtedly accelerates progressive scarring of renal parenchyma, but the relationship of hypertension and arterionephrosclerosis is not simple and linear [11] In a large series of renal biopsies in patients with essential hypertension, arterionephrosclerosis was present in the vast majority, and the severity of arteriolar sclerosis correlated significantly with level of diastolic blood pressure [9] However, in several large autopsy series of patients with presumed benign hypertension, significant renal lesions were rare [4, 5] Further, the level of blood pressure does not directly predict degree of end-organ damage: African-Americans have higher risk for more severe end-organ damage at any level of blood pressure [2] The African American Study of Kidney Disease (AASK) trial showed that African-Americans with presumed arterionephrosclerosis indeed did not have other lesions, by renal biopsy, but the global sclerosis was severe and did not correlate with vascular sclerosis [12] It is possible that underlying microvascular disease causes the hypertension and the renal disease in susceptible patients In a large study of patients without clinically evident kidney disease at baseline, even relatively modest elevation in blood pressure was an independent risk factor for development of end-stage kidney disease [13] Underlying causes in addition to direct hemodynamic injury could include possible genetic and structural components, such as decreased nephron number and consequently fewer, but enlarged glomeruli [14] Whether hypertension can cause kidney scarring, or a primary microvascular renal injury causes the hypertension, which in turn accelerates the sclerosis, has not been proven Apolipoprotein L1 allele variants are tightly linked to excess arterionephrosclerosis, focal segmental glomerulosclerosis, and HIVassociated nephropathy, but not diabetic nephropathy in African-Americans [15] The ApoL1 allele variant confers protection against some trypanosomes, which could have a survival advantage and thus, by natural selection, have led to its high prevalence in African-Americans The mechanisms of increased risk of kidney disease are unknown [16] Our data suggest a different phenotype of scarring in hypertension-attributable nephrosclerosis in African-Americans vs Caucasians, with solidified global glomerulosclerosis prevalent in the former, contrasting with the obsolescent type (see above) in Caucasians [17] The AASK trial has shown that angiotensin-converting enzyme inhibitors (ACEIs) are effective in protecting renal function in AfricanAmericans, although multiple additional drugs were needed to achieve blood pressure control [18] Cholesterol Emboli 129 Fig 10.3 Cholesterol emboli in artery with surrounding mononuclear and early fibrotic reaction (PAS) Cholesterol Emboli Introduction/Clinical Setting Patients with significant atherosclerosis are also at risk for cholesterol embolization due to dislodgment of atheromatous plaque material These emboli shower organs downstream from the site of origin in the aorta, and thus often involve the kidney, skin, gastrointestinal tract, adrenals, pancreas, and testes Cholesterol emboli may occur spontaneously or after an invasive vascular procedure This entity mimics vasculitis clinically and presents with acute renal failure, new-onset or exacerbated hypertension, and eosinophilia [19–21] Cholesterol emboli may underlie 5–10 % of all acute renal failure cases [22] In some patients, there is associated presumed secondary FSGS, with proteinuria Prognosis is generally poor, with older series reporting about 60–80 % mortality at year, with improvement with more aggressive supportive therapy in recent series [22] Pathologic Findings Cholesterol crystals usually lodge in and occlude interlobular size arteries (Fig 10.3) The crystals themselves are dissolved by processing of tissue, but cleft-shaped empty spaces remain, with surrounding mononuclear cell reaction, which over weeks organizes to fibrous tissue Vessels typically show associated arteriosclerosis, with proportional tubulointerstitial fibrosis and glomerulosclerosis 130 10 Nephrosclerosis and Hypertension [20, 21, 23] The cholesterol emboli are very focally distributed, and serial section analysis may be necessary to detect diagnostic lesions Immunofluorescence and electron microscopy not show any specific lesions Scleroderma (Progressive Systemic Sclerosis) Introduction/Clinical Setting Scleroderma is a multisystem disease that affects the skin, the GI tract, the lung, the heart, and the kidney Scleroderma is classified as a limited or diffuse cutaneous type [24] In the limited form, the disease manifests in hands, arms, and face with Raynaud’s phenomenon preceding fibrosis Diffuse cutaneous scleroderma involves the skin and one or more internal organs, most often kidneys, esophagus, heart, and lungs Kidney involvement occurs in approximately 60–70 % of patients Scleroderma renal crisis, manifest by malignant hypertension, acute kidney injury, and some even with infarcts, previously was observed in approximately 20 % of patients with scleroderma but may be decreasing due to widespread use of angiotensin-converting enzyme inhibitors in these patients [25, 26] Age at onset of systemic sclerosis is 30–50 years, and females are affected more than males Patients present with renal manifestations of acute kidney injury and malignant hypertension and may have significant proteinuria acutely Pathologic Findings Gross Findings/Light Microscopy Grossly, petechial hemorrhages or even renal infarcts may be present in patients with scleroderma renal crisis, similar to hemolytic uremic syndrome or malignant hypertension Microscopically, there is fibrinoid necrosis of afferent arterioles Interlobular arteries show intimal thickening, proliferation of endothelial cells, and edema Red blood cell fragments are often present within the injured vessel wall, and there may be vessel wall necrosis and/or fibrin thrombi within vessels Glomeruli may show ischemic collapse or fibrinoid necrosis In chronic injury, arterioles show reduplication of the elastic internal lamina, the so-called onion-skin pattern (Fig 10.4) Tubules may show degeneration and even necrosis, especially in scleroderma crisis Tubulointerstitial fibrosis develops with chronic injury [23, 25] Immunofluorescence Microscopy There are no immune complexes, although sclerotic segments of glomeruli may show IgM and C3 Necrosed vessels may show fibrin and fibrinogen Electron Microscopy There is corrugation of the GBM and increased lucency of the lamina rara interna, without immune deposits Thus, the pathologic appearance of scleroderma overlaps with that of malignant hypertension and thrombotic microangiopathy (TMA) as seen in hemolytic uremic Scleroderma (Progressive Systemic Sclerosis) 131 Fig 10.4 Onion-skin appearance in scleroderma with concentric intimal proliferation and fibrosis and mucoid change (Jones silver stain) syndromes (HUS) (see Chap 11) Idiopathic malignant hypertension tends to involve smaller vessels, that is, afferent arterioles, whereas scleroderma may extend to interlobular size and larger vessels, and the TMA in HUS typically involves primarily glomeruli However, distinction of scleroderma and malignant hypertension solely on morphologic grounds is not feasible, and clinicopathologic correlation is required for specific diagnosis Etiology/Pathogenesis The pathogenesis of scleroderma is probably immune with unknown inciting events Endothelial injury occurs early in scleroderma patients, although the inciting injury is unknown Endothelial damage and vacuolization is followed by perivascular mononuclear infiltrates, obliteration of the microvasculature, and loss of capillaries Excess collagen accumulation then ensues, linked to increased profibrotic factors Autoantibodies are often present, including anti-topoisomerase I, anti-centromere, and anti-RNA polymerase, each present in 25 % Only one of these markers may be positive in any one patient Some studies have demonstrated cytotoxic anti-endothelial factors in serum from scleroderma patients Imbalance of vasodilators (e.g., nitric oxide, vasodilatory neuropeptides such as calcitonin gene-related peptide and substance P) and vasoconstrictors (e.g., endothelin-1, serotonin, thromboxane A2) has been described in scleroderma patients Prolonged vasoconstriction could contribute to structural changes and fibrosis in the kidney as well A defect in circulating endothelial progenitor cells in scleroderma patients has been proposed to underlie deficiency of vasculogenesis and repair in response to endothelial injury, contributing to sclerosis [24, 27] 132 10 Nephrosclerosis and Hypertension References Blythe WB, Maddux FW (1991) Hypertension as a causative diagnosis of patients entering end-stage renal disease programs in the United States from 1980 to 1986 Am J Kidney Dis 18:33–37 Toto RB (2003) Hypertensive nephrosclerosis in African Americans Kidney Int 64: 2331–2341 Lopes AA, Port FK, James SA, Agodoa L (1993) The excess risk of treated end-stage renal disease in blacks in the United States J Am Soc Nephrol 3:1961–1971 Olson JL (1998) Hypertension: essential and secondary forms In: Jennette JC, Olson JL, Schwartz M, Silva FG (eds) Heptinstall’s pathology of the kidney, 5th edn Lippincott-Raven, Philadelphia, pp 943–1001 Kincaid-Smith P, Whitworth JA (1987) Hypertension and the kidney In: Kincaid-Smith P, Whitworth JA (eds) The kidney: a clinicopathologic study Blackwell, Melbourne, p 131 Sommers SC, Relman AS, Smithwick RH (1958) Histologic studies of kidney biopsy specimens from patients with hypertension Am J Pathol 34:685–713 Katz SM, Lavin L, Swartz C (1979) Glomerular lesions in benign essential hypertension Arch Pathol Lab Med 103:199–203 McManus JFA, Lupton CH Jr (1960) Ischemic obsolescence of renal glomeruli: the natural history of the lesions and their relation to hypertension Lab Invest 9:413–434 Böhle A, Wehrmann M, Greschniok A, Junghans R (1998) Renal morphology in essential hypertension: analysis of 1177 unselected cases Kidney Int Suppl 67:S205–S206 10 Böhle A, Ratschek M (1982) The compensated and decompensated form of benign nephrosclerosis Pathol Res Pract 174:357–367 11 Meyrier A, Simon P (1996) Nephroangiosclerosis and hypertension: things are not as simple as you might think Nephrol Dial Transplant 11:2116–2120 12 Fogo A, Breyer JA, Smith MC, Cleveland WH, Agodoa L, Kirk KA, Glassock R (1997) Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) trial AASK Pilot Study Investigators Kidney Int 51:244–252 13 Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C (2005) Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease Arch Intern Med 165:923–928 14 Keller G, Zimmer G, Mall G, Ritz E, Amann K (2003) Nephron number in patients with primary hypertension N Engl J Med 348:101–108 15 Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans Science 329:841–845 16 Kopp JB (2013) Rethinking hypertensive kidney disease: arterionephrosclerosis as a genetic, metabolic, and inflammatory disorder Curr Opin Nephrol Hypertens 22:266–272 17 Marcantoni C, Ma L-J, Federspiel C, Fogo AB (2002) Hypertensive nephrosclerosis in African-Americans vs Caucasians Kidney Int 62:172–180 18 Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas M, Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Y, Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J, Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, Middleton J, Miller ER III, Norris K, O'Connor D, Ojo A, Phillips RA, Pogue V, Rahman M, Randall OS, Rostand S, Schulman G, Smith W, Thornley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S, African American Study of Kidney Disease and Hypertension (AASK) Study Group (2001) Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial JAMA 285:2719–2728 References 133 19 Fine MJ, Kapoor W, Falanga V (1987) Cholesterol crystal embolization: a review of 221 cases in the English literature Angiology 38:769–784 20 Greenberg A, Bastacky SI, Iqbal A, Borochovitz D, Johnson JP (1997) Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinico- pathological correlations Am J Kidney Dis 29:334–344 21 Fogo A, Stone WJ (1998) Atheroembolic renal disease In: Martinez-Maldonado M (ed) Hypertension and renal disease in the elderly Blackwell Scientific, Cambridge, MA, pp 261–271 22 Scolari F, Ravani P (2010) Atheroembolic renal disease Lancet 375:1650–1660 23 Leinwand I, Duryee AW, Richter MN (1954) Scleroderma (based on study of over 150 cases) Ann Intern Med 41:1003–1041 24 Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma N Engl J Med 360:1989–2003 25 Donohoe JF (1992) Scleroderma and the kidney Kidney Int 41:462–477 26 Steen VD, Medsger TA Jr (2000) Long-term outcomes of scleroderma renal crisis Ann Intern Med 133:600–603 27 Kuwana M, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y (2004) Defective vasculogenesis in systemic sclerosis Lancet 364:603–610 216 20 Allograft Rejection 51 Sijpkens YW, Joosten SA, Wong MC, Dekker FW, Benediktsson H, Bajema IM, Bruijn JA, Paul LC (2004) Immunologic risk factors and glomerular C4d deposits in chronic transplant glomerulopathy Kidney Int 65:2409–2418 52 Baid-Agrawal S, Farris AB 3rd, Pascual M, Mauiyyedi S, Farrell ML, Tolkoff-Rubin N, Collins AB, Frei U, Colvin RB (2011) Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy Kidney Int 80:879–885 53 Colvin RB, Nickeleit V (2006) Renal transplant pathology In: Jennette JC, Olson JL, Schwartz MM, Silva FG (eds) Heptinstall’s Pathology of the kidney, 6th edn Lippincott-Raven, Philadelphia, pp 1347–1490 54 Ivanyi B, Kemeny E, Rago P, Lazar N, Boda K, Morvay Z, Szenohradszky P, Szederkenyi E (2011) Peritubular capillary basement membrane changes in chronic renal allograft rejection: comparison of light microscopic and ultrastructural observations Virchows Arch 459:321–330 55 Jeannet M, Pinn VW, Flax MH, Winn HJ, Russell PS (1970) Humoral antibodies in renal allotransplantation in man N Engl J Med 282:111–117 56 Pelletier RP, Hennessy PK, Adams PW, VanBuskirk AM, Ferguson RM, Orosz CG (2002) Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidneypancreas transplantation Am J Transplant 2:134–141 57 Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, Pratschke J, Rudolph B, Schmidt D, Salama A, Schonemann C (2009) Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts Transplantation 87:1505–1513 58 Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, Salvatierra O Jr (2003) Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling N Engl J Med 349:125–138 59 Einecke G, Reeve J, Mengel M, Sis B, Bunnag S, Mueller TF, Halloran PF (2008) Expression of B cell and immunoglobulin transcripts is a feature of inflammation in late allografts Am J Transplant 8:1434–1443 60 Thaunat O, Patey N, Gautreau C, Lechaton S, Fremeaux-Bacchi V, Dieu-Nosjean MC, Cassuto-Viguier E, Legendre C, Delahousse M, Lang P, Michel JB, Nicoletti A (2008) B cell survival in intragraft tertiary lymphoid organs after rituximab therapy Transplantation 85:1648–1653 61 Hirohashi T, Chase CM, Della Pelle P, Sebastian D, Alessandrini A, Madsen JC, Russell PS, Colvin RB (2012) A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody Am J Transplant 12:313–321 62 Loupy A, Hill GS, Suberbielle C, Charron D, Anglicheau D, Zuber J, Timsit MO, Duong JP, Bruneval P, Vernerey D, Empana JP, Jouven X, Nochy D, Legendre CH (2011) Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA) Am J Transplant 11:56–65 63 Sis B, Jhangri GS, Bunnag S, Allanach K, Kaplan B, Halloran PF (2009) Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining Am J Transplant 9:2312–2323 64 Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, Einecke G, Chang J, Halloran PF (2010) NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection Am J Transplant 10:1812–1822 65 Takemoto SK, Zeevi A, Feng S, Colvin RB, Jordan S, Kobashigawa J, Kupiec-Weglinski J, Matas A, Montgomery RA, Nickerson P, Platt JL, Rabb H, Thistlethwaite R, Tyan D, Delmonico FL (2004) National conference to assess antibody-mediated rejection in solid organ transplantation Am J Transplant 4:1033–1041 66 Smith RN, Kawai T, Boskovic S, Nadazdin O, Sachs DH, Cosimi AB, Colvin RB (2008) Four stages and lack of stable accommodation in chronic alloantibody-mediated renal allograft rejection in Cynomolgus monkeys Am J Transplant 8:1662–1672 67 Gloor JM, Stegall MD (2007) ABO incompatible kidney transplantation Curr Opin Nephrol Hypertens 16:529–534 Calcineurin Inhibitor Toxicity, Polyomavirus, and Recurrent Disease 21 Calcineurin Inhibitor Toxicity (CIT) Introduction/Clinical Setting Cyclosporin A (CsA) and tacrolimus have greatly improved graft survival since their introduction in the 1980 and 1990s, respectively While the drugs are structurally unrelated, their mechanism of immunosuppression is remarkably similar The dramatic immunosuppressive and nephrotoxic effects of CsA and tacrolimus are largely explained by their calcineurin inhibition The pathology of CsA and tacrolimus toxicity is pathologically indistinguishable Pathologic Findings There are three pathologic forms of toxicity: acute nephrotoxicity, chronic nephrotoxicity, and thrombotic microangiopathy (hemolytic-uremic syndrome) Each can also arise in native kidneys in patients on CsA or tacrolimus for other reasons Acute Tubulopathy The biopsy features of acute toxicity range from no morphologic abnormality to acute tubular injury or marked tubular vacuolization and vascular smooth muscle apoptosis (Fig 21.1) The proximal tubules show loss of brush borders and isometric clear vacuolization (defined as cells filled with uniformly sized vacuoles) The vacuoles, much smaller than the nucleus, contain clear aqueous fluid rather than lipid and are indistinguishable from those caused by osmotic diuretics Immunofluorescence microscopy is negative By electron microscopy, the vacuoles are dilated endoplasmic reticulum and appear empty [1] These lesions are reversible with decreased dosage A.B Fogo et al., Fundamentals of Renal Pathology, DOI 10.1007/978-3-642-39080-7_21, © Springer-Verlag Berlin Heidelberg 2014 217 218 21 Calcineurin Inhibitor Toxicity, Polyomavirus, and Recurrent Disease Fig 21.1 Acute calcineurin inhibitor toxicity, showing isometric vacuolization of proximal tubules (H&E stain) Fig 21.2 Chronic calcineurin inhibitor toxicity Peripheral nodules of hyaline are in an arteriole (black arrow) Conventional subendothelial hyaline is present (blue arrow), as well as advanced transmural hyaline deposits (gray arrow) PAS stain Arteriolopathy A spectrum of acute and chronic arteriolopathy has been described by Mihatsch, ranging from acute, focal myocyte necrosis and mucoid intimal thickening to indolent nodular hyaline deposits (Fig 21.2) [2] The characteristic features are individual smooth muscle cell degeneration, vacuolization, necrosis, and loss The myocytes are replaced by hyaline deposits, which are classically in a beaded pattern in the media The usual hyaline deposits in hypertension or diabetes are subendothelial or transmural The endothelial or smooth muscle cells may be vacuolated Later biopsies show progressive scarring of arterioles, intimal fibrosis, and segmental glomerular obsolescence Immunofluorescence of early lesions may show that the vessels have deposits of immunoglobulin M (IgM), C3, and fibrin Electron microscopy shows apoptosis or necrosis of smooth muscle cells and replacement with hyaline material Focal myocyte necrosis in the media of small arteries, in the absence of intimal changes, is regarded as a reliable indicator of CsA toxicity [3] However, Calcineurin Inhibitor Toxicity (CIT) 219 Fig 21.3 Acute calcineurin inhibitor toxicity due to tacrolimus Marked mucoid intimal thickening is present with a sparse mononuclear infiltrate and numerous trapped red cell fragments (arrow) while nodular peripheral hyaline deposits are more prevalent in biopsies from patients on CNI, they also occur with some frequency in patients who have never received these drugs [4] Thrombotic Microangiopathy Although more prevalent with higher doses of CsA in the 1980s, thrombotic microangiopathy (Fig 21.3) still occurs under current regimens, even with careful attention to blood CsA levels By 1994, the prevalence of CsA-associated thrombotic microangiopathy had decreased to 0.9 %, accounting for 26 % of the cases of thrombotic microangiopathy after renal transplantation (acute rejection, probably humoral, accounted for 53 % and recurrent thrombotic microangiopathy 16 %) [5] Patients typically present with acute renal failure, thrombocytopenia, microangiopathic hemolytic anemia, elevated lactic dehydrogenase, and hyperbilirubinemia Despite these characteristic features, the clinical syndrome is not often recognized before biopsy Those without systemic signs (thrombocytopenia, hemolysis) considerably better [6] The pathologic changes are the same as in thrombotic microangiopathy from other causes, although in the allograft the differential diagnosis with endarteritis can be challenging Loose intimal thickening and trapped red cells are useful discriminators Differential Diagnosis The criteria for the morphologic distinction of calcineurin inhibitor toxicity (CIT) and rejection have received much attention Interstitial infiltrates are minimal in autologous kidneys with nephrotoxicity, but are common in early allografts, and have no differential value unless minimal Patients with rejection typically have a 220 21 Calcineurin Inhibitor Toxicity, Polyomavirus, and Recurrent Disease diffuse, interstitial mononuclear cell infiltrate, whereas patients with CIT and those with stable function have only focal mononuclear cell infiltrates [7] Endarteritis is found rarely, if ever, in CIT (0–1 %) and is the most discriminating feature between acute rejection and CIT Only the finding of endarteritis allowed the identification of rejection with any certainty [8] This agrees with my experience and that of others [3] Endothelial and medial smooth muscle cell vacuolization has been noted in CIT, best appreciated by electron microscopy The frequency of vacuolization probably does not distinguish CIT from stable grafts [7] Polyomavirus Introduction/Clinical Setting The BK polyomavirus was originally isolated from B K., a Sudanese patient who had distal donor ureteral stenosis months after a living related transplant [9] BK virus is related to JC virus (which also inhabits the human urinary tract) and to simian kidney virus SV-40 These viruses are members of the papovavirus group, which includes the papillomaviruses The BK virus commonly infects urothelium but rarely causes morbidity in immunocompetent individuals However, in renal transplant recipients three lesions have been attributed to BK virus: hemorrhagic cystitis, ureteral stenosis, and acute interstitial nephritis [10] Pathologic Findings Light Microscopy The kidney shows interstitial nephritis, with mononuclear cells infiltrating the interstitium and tubules, often with a prominent component of plasma cells, which also may be occasionally found in tubules (Fig 21.4) [11] Polyoma infection is initially suggested by the occurrence of markedly enlarged tubular epithelial cells with nuclear atypia and chromatin basophilia The recognition of viral nuclear inclusions is the key step in diagnosis The affected nuclei are usually enlarged and tend to be grouped in tubules, particularly collecting ducts in the cortex and outer medulla, and can often be spotted at low power The mononuclear interstitial infiltrate is associated with the infected cells Routine urine cytology readily reveals characteristic viral inclusions (decoy cells) Discrimination between acute cellular rejection and polyomavirus infection can be difficult Among the reliable indicators of a component of rejection are endarteritis and C4d deposition If the inflammation is found primarily in areas of viral antigen, I believe this favors polyoma as the predominate disease Immunohistochemistry Polyomavirus large T antigen can be demonstrated in tubular epithelial cells, typically in clusters, and especially in collecting ducts (Fig 21.5) Monoclonal antibodies are Polyomavirus 221 Fig 21.4 Polyomavirus interstitial nephritis Plasma cells are abundant and nuclear inclusions are evident (arrow) (H&E stain) Fig 21.5 Polyomavirus interstitial nephritis Viral antigens are demonstrated by immunoperoxidase stains in tubular epithelial nuclei using a monoclonal antibody to SV-40 large T antigen commercially available that react with BK specific determinants and with the large T antigen of several polyoma species We have obtained good results with paraffin techniques These techniques also work in urine cytology preparations Immunofluorescence shows granular deposits of IgG and C3/C4d along the GBM in about half of the patients [12, 13] The nature of the antigen (viral, autoantigen) is uncertain Both BK and JC viruses can cause interstitial nephritis and are detected with the usual antibody to anti-large T antigen However, JC alone rarely causes graft failure [14] Electron Microscopy Electron microscopy reveals the characteristic intranuclear viral particles of 30–40-nm diameter in tubular epithelium (Fig 21.6) Aggregates of polyomavirus and matrix, termed “haufen,” are evident in negatively stained urine sediment by electron microscopy [15] 222 21 Calcineurin Inhibitor Toxicity, Polyomavirus, and Recurrent Disease Fig 21.6 Polyomavirus interstitial nephritis Electron microscopy reveals the 30–40-nm viral particles in tubular nuclei (bar = 100 nm) Pathogenesis A promoting role for rejection appears likely, because polyomavirus interstitial nephritis is quite uncommon in recipients of heart, liver, or lung transplants Alternatively, the allograft kidney may serve as a “sanctuary” for the virus, since T-cell killing of virally infected cells requires self-major histocompatibilitycomplex (MHC) antigens to be expressed on the target cells Most recent cases have arisen in patients on tacrolimus or mycophenolate mofetil (MMF) Among centers using tacrolimus and MMF, the frequency of polyoma-associated interstitial nephritis (AIN) is 3–5 % [15–18] Recovery, without reduction of immunosuppression, is not common (69 % graft loss) With reduction of immunosuppression, graft survival is likely (>95 %), but functional recovery is poor (38 % have residual Cr >3.0 mg/dL) [16, 17] Protocol biopsies and monitoring of blood/urine for virus should permit earlier treatment and improved outcome The use of polymerase chain reaction (PCR) to detect viral DNA in the circulation helps distinguish those with interstitial nephritis from noninvasive urothelial shedding of the virus [14, 18] Antivirals, such as cidofovir, have had limited success Recurrent Renal Disease The frequency and clinical significance of recurrence varies with the disease [19] Recurrent disease is the third most common cause of graft loss in patients whose original disease was glomerulonephritis [20] The diseases that recur commonly are dense deposit disease (>80 %), monoclonal immunoglobulin deposition disease (70–85 %), diabetes (>50 %), fibrillary glomerulonephritis (GN) (~50 %), IgA nephropathy (13–50 %), primary focal glomerular sclerosis (20–40 %), atypical hemolytic-uremic syndrome (>25 %), type I membranoproliferative GN (20–50 %), and lupus nephritis (>25 %) However, only have a significant impact on graft References 223 survival: MPGN, primary FSGS, and atypical HUS [21] The diagnosis of recurrence requires accurate classification of the original disease and lesions that differ from chronic allograft glomerulopathy References Mihatsch MJ, Thiel G, Ryffel B (1988) Cyclosporine nephrotoxicity Adv Nephrol Necker Hosp 17:303–320 Mihatsch MJ, Gudat F, Ryffel B, Thiel G (1994) Cyclosporine nephropathy In: Tisher CC, Brenner BM (eds) Renal pathology: with clinical and functional correlations, 2nd edn J.B Lippincott, Philadelphia, pp 1641–1681 Taube DH, Neild GH, Williams DG, Cameron JS, Hartley B, Ogg CS, Rudge CJ, Welsh KI (1985) Differentiation between allograft rejection and cyclosporin nephrotoxicity in renal transplant recipients Lancet 2(8448):171–174 Snanoudj R, Royal V, Elie C, Rabant M, Girardin C, Morelon E, Kreis H, Fournet JC, Noel LH, Legendre C (2011) Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy Am J Transplant 11:2635–2646 Candinas D, Keusch G, Schlumpf R, Burger HR, Gmur J, Largiader F (1994) Hemolyticuremic syndrome following kidney transplantation: prognostic factors Schweiz Med Wochenschr 124:1789–1799 Schwimmer J, Nadasdy TA, Spitalnik PF, Kaplan KL, Zand MS (2003) De novo thrombotic microangiopathy in renal transplant recipients: a comparison of hemolytic uremic syndrome with localized renal thrombotic microangiopathy Am J Kidney Dis 41:471–479 Neild GH, Taube DH, Hartley RB, Bignardi L, Cameron JS, Williams DG, Ogg CS, Rudge CJ (1986) Morphological differentiation between rejection and cyclosporin nephrotoxicity in renal allografts J Clin Pathol 39:152–159 Sibley RK, Rynasiewicz J, Ferguson RM, Fryd D, Sutherland DE, Simmons RL, Najarian JS (1983) Morphology of cyclosporine nephrotoxicity and acute rejection in patients immunosuppressed with cyclosporine and prednisone Surgery 94:225–234 Gardner SD, Field AM, Coleman DV, Hulme B (1971) New human papovavirus (B.K.) isolated from urine after renal transplantation Lancet 1:1253–1257 10 Randhawa P, Brennan DC (2006) BK virus infection in transplant recipients: an overview and update Am J Transplant 6:2000–2005 11 Colvin RB, Nickeleit V (2006) Renal transplant pathology In: Jennette JC, Olson JL, Schwartz MM, Silva FG (eds) Heptinstall’s pathology of the kidney, 6th edn Lippincott-Raven, Philadelphia, pp 1347–1490 12 Bracamonte E, Leca N, Smith KD, Nicosia RF, Nickeleit V, Kendrick E, Furmanczyk PS, Davis CL, Alpers CE, Kowalewska J (2007) Tubular basement membrane immune deposits in association with BK polyomavirus nephropathy Am J Transplant 7:1552–1560 13 Hever A, Nast CC (2008) Polyoma virus nephropathy with simian virus 40 antigen-containing tubular basement membrane immune complex deposition Hum Pathol 39:73–79 14 Drachenberg CB, Hirsch HH, Papadimitriou JC, Gosert R, Wali RK, Munivenkatappa R, Nogueira J, Cangro CB, Haririan A, Mendley S, Ramos E (2007) Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation Transplantation 84:323–330 15 Singh HK, Andreoni KA, Madden V, True K, Detwiler R, Weck K, Nickeleit V (2009) Presence of urinary Haufen accurately predicts polyomavirus nephropathy J Am Soc Nephrol 20:416–427 16 Ramos E, Hirsch HH (2006) Polyomavirus-associated nephropathy: updates on a persisting challenge Transpl Infect Dis 8:59–61 224 21 Calcineurin Inhibitor Toxicity, Polyomavirus, and Recurrent Disease 17 Drachenberg CB, Hirsch HH, Ramos E, Papadimitriou JC (2005) Polyomavirus disease in renal transplantation: review of pathological findings and diagnostic methods Hum Pathol 36:1245–1255 18 Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, Thiel G, Mihatsch MJ, Hirsch HH (2000) Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy N Engl J Med 342:1309–1315 19 Colvin RB, Chang A, Farris AB, Kambham N, Cornell LD, Meehan SM, Liapis H, Bonsib SM, Seshan S, Vasilyev A, Jain S (2011) Diagnostic pathology: kidney diseases Amirsys Publishing, Salt Lake City 20 Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ (2002) Risk of renal allograft loss from recurrent glomerulonephritis N Engl J Med 347:103–109 21 Hariharan S, Adams MB, Brennan DC, Davis CL, First MR, Johnson CP, Ouseph R, Peddi VR, Pelz CJ, Roza AM, Vincenti F, George V (1999) Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR) Transplantation 68:635–641 Index A Acute antibody-mediated rejection (Acute AMR) clinical features, 203 clinicopathologic correlations, 206 pathogenesis, 205–206 pathologic findings immunofluorescence microscopy, 204–205 light microscopy, 203–204 Acute cellular rejection (ACR) clinical setting, 199 pathogenesis, 202–203 pathologic findings electron microscopy, 202 immunofluorescence microscopy, 202 light microscopy, 199–202 Acute humoral rejection See Acute antibody-mediated rejection (Acute AMR) Acute interstitial nephritis (AIN) clinical setting, 155 clinicopathologic correlations, 158 etiology/pathogenesis, 157–158 pathologic findings, 155–156 Acute tubular necrosis (ATN) ischemic pathogenesis, 170 pathologic findings, 167–170 toxic, 171 Afferent arterioles, 3, African American Study of Kidney Disease (AASK) trial, 128 Alcoholic Bouin’s solution, Alport syndrome clinical setting, 79 etiology/pathogenesis, 81–82 pathologic findings electron microscopy, 81 immunofluorescence microscopy, 80 light microscopy, 80 Amyloidosis clinical setting, 185 etiology/pathogenesis, 187–189 pathologic findings electron microscopy, 187, 188 immunofluorescence microscopy, 187 light microscopy, 185–187 Angiotensin-converting enzyme inhibitors (ACEI), 76 Anti-glomerular basement membrane antibody, 15 Anti-glomerular basement membrane disease, 109 clinicopathologic correlations, 111–112 pathologic findings electron microscopy, 110 immunofluorescence microscopy, 110, 111 light microscopy, 109–110 Antineutrophil cytoplasmic autoantibody (ANCA) disease, 108 clinical setting, 112 clinicopathologic correlations, 116–117 etiology/pathogenesis, 116 pathologic findings, 112–116 Anti-vascular endothelial derived growth factor (VEGF) agents, 140 Apoptosis, 170 Arcuate arteries, Arterionephrosclerosis clinical setting, 125–126 etiology/pathogenesis, 128 pathologic findings electron microscopy, 128 immunofluorescence, 127 light microscopy, 126–127 A.B Fogo et al., Fundamentals of Renal Pathology, DOI 10.1007/978-3-642-39080-7, © Springer-Verlag Berlin Heidelberg 2014 225 226 B Banff system, 199 Basket-weaving appearance, GBM, 81 Bence Jones cast nephropathy clinical setting, 175 pathogenesis, 177–178 pathologic findings immunohistochemistry and electron microscopy, 177 light microscopy, 176–177 Bence Jones proteinuria, 176 Benign familial hematuria See Thin basement membrane abnormality Bowman’s space, C Calcineurin inhibitor toxicity (CIT) clinical setting, 217 diagnosis, 219–220 pathologic findings acute tubulopathy, 217–218 arteriolopathy, 218–219 thrombotic microangiopathy, 219 Calyces, C3 glomerulonephritis clinical setting, 31 etiology/pathogenesis, 41 pathologic findings electron microscopy, 36–37, 39 immunofluorescence microscopy, 36 light microscopy, 34, 35 Cholesterol emboli, 129–130 Chronic antibody-mediated rejection (Chronic AMR) clinical setting, 206–207 diagnosis, 212 pathogenesis, 211–212 pathologic findings electron microscopy, 210–211 immunofluorescence microscopy, 209–210 light microscopy, 208–209 Chronic humoral rejection See Chronic antibody-mediated rejection (Chronic AMR) Chronic interstitial nephritis clinical setting, 161 etiology/pathogenesis, 163–165 pathologic findings gross findings, 161–162 light microscopy, 162–163 Index Chronic pyelonephritis, 164 Circumferential cellular interposition, 32 Columns of Bertin, 3–4 Cortex, 3–5 C1q nephropathy, 54 Crescents, 13 Cryoglobulinemic vasculitis, 109 Cryo-plugs, in capillary lumina, 39, 40 Cyclosporin A (CsA), 217 D Decompensated arterionephrosclerosis, 126 Dense deposit disease (DDD) clinicopathologic correlations, 41 etiology/pathogenesis, 40–41 pathologic findings electron microscopy, 36, 38 immunofluorescence microscopy, 34–35 light microscopy, 34 Diabetic nephropathy clinical setting, 143 etiology/pathogenesis, 150 glomerular classification, 149 pathologic classification, 149–150 pathologic findings electron microscopy, 148, 149 immunofluorescence microscopy, 147–148 light microscopy, 143–147 Diffuse diabetic glomerulosclerosis, 144–145 Diffuse lupus nephritis, 94–97 Diffuse segmental lesions, 94 Distal tubule, 8, 167–168 E Electron microscopy acute cellular rejection, 202 acute postinfectious glomerulonephritis, 65 Alport syndrome, 81 amyloidosis, 187, 188 anti-glomerular basement membrane disease, 110 Bence Jones cast nephropathy, 177 C3 glomerulonephritis, 36–37, 39 Index chronic antibody-mediated rejection, 210–211 dense deposit disease, 36, 38 diabetic nephropathy, 148, 149 FSGS, 50 immunoglobulin A nephropathy and vasculitis, 73–74 light and heavy-chain-deposition disease, 181–182 membranous nephropathy, 24–26 minimal change disease, 50 MPGN, 36–39 scleroderma, 130–131 thin basement membrane, 83 thrombotic microangiopathy, 137–138 Endarteritis, 200–203 Endocapillary proliferation, 62, 101 Exudative glomerulonephritis, 62 F Fibrillary glomerulonephritis clinical correlations, 193–194 clinical setting, 191 pathologic findings, 191–192 Focal lupus nephritis, 91–94 Focal segmental glomerulosclerosis (FSGS) clinical setting, 45 clinicopathologic correlations, 52–54 C1q nephropathy, 54 etiology/pathogenesis, 50 pathologic findings electron microscopy, 50 immunofluorescence microscopy, 49 light microscopy, 45–49 secondary, 55 Foot process effacement, 13, 25 chronic AMR, 210 FSGS, 51, 54 MCD, 50 MPGN, 36 G Giant cell arteritis, 108 Glomerular hyalinization, 12 Glomerular hyalinosis, 146 Glomerular scarring, 12 Goodpasture’s syndrome See Anti-glomerular basement membrane disease 227 H Heavy-chain-deposition disease See Light-chain-deposition disease Hemolytic uremic syndrome (HUS) characterization, 135 clinicopathologic correlations, 140–141 etiology/pathogenesis, 138–140 pathologic findings electron microscopy, 137–138 immunofluorescence microscopy, 137 light microscopy, 135–137 Henoch-Schönlein purpura See Immunoglobulin A (IgA) nephropathy and vasculitis Humoral immunity, AIN, 157 Hyaline droplets, 13 Hyalinosis, 45, 47, 146 Hyperacute rejection, 206, 207 Hypertension arterionephrosclerosis, 125–128 cholesterol emboli, 129–130 scleroderma, 130–131 I Immune complex vasculitis, 109 Immunofluorescence microscopy acute antibody-mediated rejection, 204–205 acute cellular rejection, 202 acute postinfectious glomerulonephritis, 64–65 Alport syndrome, 80 amyloidosis, 187 anti-glomerular basement membrane disease, 110, 111 C3 glomerulonephritis, 36 chronic antibody-mediated rejection, 209–210 dense deposit disease, 34–35 diabetic nephropathy, 147–148 focal segmental glomerulosclerosis, 49 immunoglobulin A nephropathy and vasculitis, 72–73 light and heavy-chain-deposition disease, 181 membranous nephropathy, 23, 24 MPGN, 34, 35 thin basement membrane, 83 thrombotic microangiopathy, 137 228 Immunoglobulin A (IgA) nephropathy and vasculitis definition, 69 etiology/pathogenesis, 74 pathologic findings electron microscopy, 73–74 immunofluorescence microscopy, 72–73 light microscopy, 69–72 Immunotactoid glomerulopathy, 193–194 Interferon-α therapy, 41 Interlobular arteries, 3–5 Interlobular veins, Interstitial capillaries, K Kawasaki disease, 108, 118 KDIGO guidelines, 76 Kimmelstiel–Wilson (K–W) nodules, 145 L Large-vessel vasculitis, 119–120 Late graft loss, 206–207 Light-chain cast nephropathy, 176 See also Bence Jones cast nephropathy Light-chain-deposition disease characterization, 179 clinical setting, 179 etiology/pathogenesis, 182 pathologic findings electron microscopy, 181–182 immunofluorescence microscopy, 181 light microscopy, 180 Light microscopy acute antibody-mediated rejection, 203–204 acute cellular rejection, 199–202 acute postinfectious glomerulonephritis, 62–64 Alport syndrome, 80 amyloidosis, 185–187 anti-glomerular basement membrane disease, 109–110 Bence Jones cast nephropathy, 176–177 C3 glomerulonephritis, 34, 35 chronic antibody-mediated rejection, 208–209 dense deposit disease, 34 diabetic nephropathy, 143–147 FSGS cellular variant, 49 classification schema, FSGS variants, 48 Index collapsing variant, 47, 48 glomerular tip lesion, 47, 49 glomerulosclerosis, 45, 46 hyalinosis, 45, 47 immunoglobulin A nephropathy and vasculitis, 69–72 light and heavy-chain-deposition disease, 180 membranous nephropathy, 22–23 minimal change disease, 45, 46 MPGN, 32–33 scleroderma, 130, 131 thrombotic microangiopathy, 135–137 Loop of Henle, Lupus glomerulonephritis, 69 Lupus nephritis active and chronic glomerular lesions, 91 challenges, 100–101 characterization, 89 clinicopathologic correlations, 102–103 etiology/pathogenesis, 101–102 ISN/RPS classification, 89, 90 pathologic findings advanced sclerosing lupus nephritis, 98 diffuse lupus nephritis, 94–97 focal lupus nephritis, 91–94 lupus podocytopathy, 98 membranous lupus nephritis, 97–98 mesangial lupus nephritis, 91, 92 tubulointerstitial lesions, 99–100 vascular lesions, 98–99 Lupus podocytopathy, 98 M Malakoplakia, 164 Medium-vessel vasculitis, 108 Membranoproliferative glomerulonephritis (MPGN) characterization, 31 clinicopathologic correlations, 41 etiology/pathogenesis, 39–40 pathologic findings electron microscopy, 36–39 immunofluorescence microscopy, 34, 35 light microscopy, 32–33 Membranous lupus nephritis, 97–98 Membranous nephropathy clinical setting, 21 clinicopathologic correlations, 27–28 Index etiology/pathogenesis, 26–27 pathologic findings electron microscopy, 24–26 immunofluorescence microscopy, 23, 24 light microscopy, 22–23 Mesangial cells, 7, 13 Mesangial lupus nephritis, 91, 92 Mesangiocapillary glomerulonephritis See Membranoproliferative glomerulonephritis (MPGN) Michaelis-Gutmann bodies, 164 Microscopic polyangiitis (MPA), 108, 114 Minimal change disease (MCD) clinical setting, 45 etiology/pathogenesis, 51–52 pathologic findings electron microscopy, 50 light microscopy, 45, 46 Monoclonal immunoglobulin deposition disease (MIDD), 150 See also Light-chain-deposition disease MPGN See Membranoproliferative glomerulonephritis (MPGN) Myeloma cast nephropathy See Bence Jones cast nephropathy N Nonreplacement phenomenon, 168, 169 O Onion-skin pattern, in scleroderma, 130, 131 Oxford classification system, IgA nephropathy, 75 P Pauci-immune crescentic glomerulonephritis, 113 Pedicles, Podocyte foot processes, 65 Polyarteritis nodosa, 108, 117–118 Polyomavirus clinical setting, 220 pathogenesis, 222 pathologic findings 229 electron microscopy, 221–222 immunohistochemistry, 220–221 light microscopy, 220, 221 Postinfectious glomerulonephritis, acute clinical setting, 61–62 clinicopathologic correlations, 67 etiology/pathogenesis, 66 pathologic findings electron microscopy, 65 immunofluorescence microscopy, 64–65 light microscopy, 62–64 Progressive systemic sclerosis, 130–131 Proliferative glomerulonephritis, 12 R Recurrent renal disease, 222–223 Reflux nephropathy, 161, 163–164 Renal allograft biopsies, 197, 198 Renal anatomy afferent arterioles, 3, arcuate arteries, Bowman’s space, collecting system, cortex, 3–5 glomeruli, 4–6 interlobular arteries, 3, interlobular veins, loop of Henle, medulla, 3–4 pathology glomeruli, 12–13 interstitium, 14 tubules, 13–14 tissue examination, 8–11 Renal diseases, pathogenic mechanisms in glomerular immunologic, 15–16 nonimmunologic, 16 tubular and interstitial injury, 16 vasculature, 16–17 Renal veins, S Scleroderma, 130–131 Sclerosis, 12 definition, 45 progressive systemic, 130–131 Size-selective barrier, Slit-pore diaphragm, 230 Small-vessel vasculitis, 119–120 Staining characteristics, renal structures, Streptococcal pyogenic exotoxin B (SpeB), 66 Systemic lupus erythematosus (SLE) See Lupus nephritis T Tacrolimus, 217 Takayasu arteritis, 108 Tamm-Horsfall protein (THP), 11–12 Thin basement membrane abnormality clinical setting, 82–83 electron microscopy, 83 etiology/pathogenesis, 84 immunofluorescence microscopy, 83 Thrombotic microangiopathies (TMA) See Hemolytic uremic syndrome (HUS); Thrombotic thrombocytopenic purpura (TTP) Thrombotic microangiopathy (TMA), 31, 219 Thrombotic thrombocytopenic purpura (TTP) characterization, 135 clinicopathologic correlations, 140–141 etiology/pathogenesis, 138–140 Index pathologic findings electron microscopy, 137–138 immunofluorescence microscopy, 137 light microscopy, 135–137 Toxic acute tubular necrosis, 171 Tram-track appearance, MPGN, 31 Transmural endarteritis, 201 Tubulointerstitial injury, 16 Tubulointerstitial lesions, 99–100 Tubulointerstitial nephritis with uveitis (TINU) syndrome, 158 Tubuloreticular inclusions (TRIs), 97 U Uromodulin, 11–12 V Verotoxin, 138–139 W Wegener’s granulomatosis, 108, 113, 115 Wire-loop lesions, 95, 97 ... Opin Nephrol Hypertens 22 :26 6 27 2 17 Marcantoni C, Ma L-J, Federspiel C, Fogo AB (20 02) Hypertensive nephrosclerosis in African-Americans vs Caucasians Kidney Int 62: 1 72 180 18 Agodoa LY, Appel... taken not A.B Fogo et al., Fundamentals of Renal Pathology, DOI 10.1007/978-3-6 42- 39080-7_ 12, © Springer-Verlag Berlin Heidelberg 20 14 143 144 12 Diabetic Nephropathy Fig 12. 1 Glomerulus from patient... 39:1569–1576 11 Østerby R (1997) Renal changes in the diabetic kidney Nephrol Dial Transplant 12: 128 2– 128 3 12 Østerby R, Hartmann A, Bangstad HJ (20 02) Structural changes in renal arterioles in type